Sertraline hydrochloride, (1S-cis)-4-(3,4 dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula:
is approved, under the trademark Zoloft®, by the U.S. Food and Drug Administration, as a serotonin re-uptake inhibitor for the treatment of depression, obsessive-compulsive disorder, panic disorder and post-traumatic disorder. Only cis sertraline is therapeutically active.
U.S. Pat. No. 4,536,518 describes a synthesis of sertraline hydrochloride from sertralone having the following formula:

The process for synthesizing sertraline from sertralone has two steps. First, sertralone is condensed with methyl amine in the presence of an acid catalyst, to yield the Schiff base of sertralone, “sertraline-1-imine”:

The imine is then reduced to sertraline. The reduction process of U.S. Pat. No. 4,536,518 involves the hydrogenation of sertraline-1-imine concentrate at room temperature for two hours over 10% Pd/C catalyst in an atmosphere of hydrogen (1 atm pressure). The product is a racemic mixture of the cis and trans diastereoisomers (“(±)-cis/trans-sertraline”) in the ratio of approximately 3 to 1. The '518 patent discloses that reduction with NaBH4 gives a cis:trans ratio of about 1:1.
Two publications, WO 01/30742 and WO 98/27050, disclose the stereoselective reduction of sertraline-imine derivatives. The publication, WO 01/30742, discloses replacing the methyl group of sertraline 1-imine with an optionally substituted bulky benzyl group to increase the cis to trans ratio during hydrogenation, followed by additional steps of converting the bulky group to a methyl group. Additionally, the publication, WO 01/30742, discloses: “The reduction may be performed using complex hydrides (e.g. NaBH4) or by hydrogenation. Reduction performed by catalytic hydrogenation tends to give better selectivity that reduction using the complex hydrides. For example, aliquots of N-[4-(3,4 dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-benzylamine were reduced with NaBH4 and Raney nickel/H2 respectively, and subsequently reductively alkylated with formaldehyde, whereafter the cis/trans ratio was analyzed. The result was a ratio of 53.8/46.2 using NaBH4 compared to 82.9/17.1 for Raney nickel/H2 which clearly demonstrates the selectivity for the catalytic hydrogenation. An even higher selectivity with a cis/trans ratio of 93.5/6.5 has been observed using palladium on carbon.”
The publication, WO 98/27050, discloses obtaining sertraline by reducing an N-oxide derivative of the imine. In Example 1, the N-oxide derivative is hydrogenated with Raney nickel catalyst, while in Example 2 a 10% palladium on carbon is used as a catalyst. A cis product with an 81% yield is obtained in both instances. According to WO 98/27050, the N-oxide group may then be removed by addition of HCl to the N-oxide compound in ethanol.
The publication, WO 01/16089, discloses a process of reductive amination of sertralone to cis and trans sertraline. In Example 1, sertralone is reduced in the presence of Raney nickel and methylamine. The yield provided in Example 1 is 48–51% of the cis isomer.
The publication, WO 99/57093, discloses a process of selective hydrogenation with a palladium catalyst pretreated with an alkyl halide. The publication discloses that the process of the '518 patent may lead to 10% of dechlorinated side products, while the process of the publication has a “total amount of said contaminated by-products . . . below 0.5%.” In regards to the cis/trans ratio, the ratio provided is 85–95% in the description of the invention. Alkyl halides however are problematic for use on an industrial scale since halogenated reagents are often not environmentally friendly.
U.S. Pat. No. 6,593,496 discloses preparing sertraline-I imine by reacting sertralone with monomethylamine and either titanium tetrachloride or molecular sieves. The hydrogenation illustrated in scheme 1 is carried out with a palladium catalyst in THF.
In US 2003/0105364, a process is provided for obtaining optically pure sertralone through chromatography. The examples do not illustrate hydrogenation.
In US 2003/0166970, a process for making (±)-sertraline with a cis/trans ratio of greater than about 3:1 is provided by hydrogenation of sertraline-1-imine at a temperature of at least about 40° C. using a palladium or a platinum catalyst.
There is a need in the art for additional processes for hydrogenation of imines for preparation of sertraline.